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1. Review of Integrin‐Targeting Biomaterials in Tissue Engineering

   https://doi.org/10.1002/adhm.202000795  

   Dhavalikar, Prachi; Robinson, Andrew; Lan, Ziyang; Jenkins, Dana; Chwatko, Malgorzata; Salhadar, Karim; Jose, Anupriya; Kar, Ronit; Shoga, Erik; Kannapiran, Aparajith; et al (September 2020, Advanced Healthcare Materials)

   Abstract The ability to direct cell behavior has been central to the success of numerous therapeutics to regenerate tissue or facilitate device integration. Biomaterial scientists are challenged to understand and modulate the interactions of biomaterials with biological systems in order to achieve effective tissue repair. One key area of research investigates the use of extracellular matrix‐derived ligands to target specific integrin interactions and induce cellular responses, such as increased cell migration, proliferation, and differentiation of mesenchymal stem cells. These integrin‐targeting proteins and peptides have been implemented in a variety of different polymeric scaffolds and devices to enhance tissue regeneration and integration. This review first presents an overview of integrin‐mediated cellular processes that have been identified in angiogenesis, wound healing, and bone regeneration. Then, research utilizing biomaterials are highlighted with integrin‐targeting motifs as a means to direct these cellular processes to enhance tissue regeneration. In addition to providing improved materials for tissue repair and device integration, these innovative biomaterials provide new tools to probe the complex processes of tissue remodeling in order to enhance the rational design of biomaterial scaffolds and guide tissue regeneration strategies. 

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2. Fibroblast clearance of damaged tissue following laser ablation in engineered microtissues

   https://doi.org/10.1063/5.0133478  

   Griebel, Megan; Vasan, Anish; Chen, Christopher; Eyckmans, Jeroen (March 2023, APL Bioengineering)

   Although the mechanisms underlying wound healing are largely preserved across wound types, the method of injury can affect the healing process. For example, burn wounds are more likely to undergo hypertrophic scarring than are lacerations, perhaps due to the increased underlying damage that needs to be cleared. This tissue clearance is thought to be mainly managed by immune cells, but it is unclear if fibroblasts contribute to this process. Herein, we utilize a 3D in vitro model of stromal wound healing to investigate the differences between two modes of injury: laceration and laser ablation. We demonstrate that laser ablation creates a ring of damaged tissue around the wound that is cleared by fibroblasts prior to wound closure. This process is dependent on ROCK and dynamin activity, suggesting a phagocytic or endocytic process. Transmission electron microscopy of fibroblasts that have entered the wound area reveals large intracellular vacuoles containing fibrillar extracellular matrix. These results demonstrate a new model to study matrix clearance by fibroblasts in a 3D soft tissue. Because aberrant wound healing is thought to be caused by an imbalance between matrix degradation and production, this model, which captures both aspects, will be a valuable addition to the study of wound healing. 

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3. Chimpanzee fibroblasts exhibit greater adherence and migratory phenotypes than human fibroblasts

   https://doi.org/10.1101/838755  

   Zintel, T.M.; Ducey, D.; Babbitt, C.C. (November 2019, bioRxiv)

   null (Ed.)

   Background and objectives Previous work has identified that gene expression differences in cell adhesion pathways exist between humans and chimpanzees. Here, we used a comparative cell biology approach to assay interspecies differences in cell adhesion phenotypes in order to better understand the basic biological differences between species’ epithelial cells that may underly the organism-level differences we see in wound healing and cancer. Methodology We used skin fibroblast cell lines from humans and chimpanzees to assay cell adhesion and migration. We then utilized published RNA-Seq data from the same cell lines exposed to a cancer / wound-healing mimic to determine what gene expression changes may be corresponding to altered cellular adhesion dynamics between species. Results The functional adhesion and migration assays revealed that chimpanzee fibroblasts adhered sooner and remained adherent for significantly longer and move into a “wound” at faster rate than human fibroblasts. The gene expression data suggest that the enhanced adhesive properties of chimpanzee fibroblasts may be due to chimpanzee fibroblasts exhibiting significantly higher expression of cell and focal adhesion molecule genes than human cells, both during a wound healing assay and at rest. Conclusions and implications Chimpanzee fibroblasts exhibit stronger adhesion and greater cell migration than human fibroblasts. This may be due to divergent gene expression of focal adhesion and cell adhesion molecules, such as integrins, laminins, and cadherins, as well as ECM proteins like collagens. This is one of few studies demonstrating that these divergences in gene expression between closely related species can manifest in fundamental differences in cell biology. Our results provide better insight into species-specific cell biology phenotypes and how they may influence more complex traits, such as cancer metastasis and wound healing. 

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4. Engineering a macroporous fibrin-based sequential interpenetrating polymer network for dermal tissue engineering

   https://doi.org/10.1039/D0BM01161D  

   Gsib, Olfat; Eggermont, Loek J.; Egles, Christophe; Bencherif, Sidi A. (December 2020, Biomaterials Science)

   null (Ed.)

   The success of skin tissue engineering for deep wound healing relies predominantly on the design of innovative and effective biomaterials. This study reports the synthesis and characterization of a new type of naturally-derived and macroporous interpenetrating polymer network (IPN) for skin repair. These biomaterials consist of a biologically active fibrous fibrin network polymerized within a mechanically robust and macroporous construct made of polyethylene glycol and biodegradable serum albumin (PEGDM- co -SAM). First, mesoporous PEGDM- co -SAM hydrogels were synthesized and subjected to cryotreatment to introduce an interconnected macroporous network. Subsequently, fibrin precursors were incorporated within the cryotreated PEG-based network and then allowed to spontaneously polymerize and form a sequential IPN. Rheological measurements indicated that fibrin-based sequential IPN hydrogels exhibited improved and tunable mechanical properties when compared to fibrin hydrogels alone. In vitro data showed that human dermal fibroblasts adhere, infiltrate and proliferate within the IPN constructs, and were able to secrete endogenous extracellular matrix proteins, namely collagen I and fibronectin. Furthermore, a preclinical study in mice demonstrated that IPNs were stable over 1-month following subcutaneous implantation, induced a minimal host inflammatory response, and displayed a substantial cellular infiltration and tissue remodeling within the constructs. Collectively, these data suggest that macroporous and mechanically reinforced fibrin-based sequential IPN hydrogels are promising three-dimensional platforms for dermal tissue regeneration. 

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5. Collagen I-Derived Extracellular Matrix Motifs Alter Fibroblast Regenerative Response

   https://doi.org/10.1159/000549101  

   Sanyaolu, Opemipo; Garza, Victoria; Santi, Athena; Romero_Uribe, Gabriela; Guda, Teja; Isaac, Alisa (October 2025, Cells Tissues Organs)

   Introduction: Damage-associated molecular patterns (DAMPs) are molecules released in response to tissue or cellular damage to facilitate tissue regeneration. This inflammatory response can occur in sterile environments and is promoted by the release of damaged extracellular components such as the extracellular matrix (ECM). DAMPs have been implicated in various stages of wound healing but have yet to be explicitly utilized for regenerative medicine by leveraging selective modulation of the inflammatory response. With this in mind, we leverage inflammation to drive tissue regeneration by utilizing DAMPs collected from the native ECM, extracellular matrix motifs (mECM). Methods: Here, mECMs were derived from UV-damaged rat tail collagen I. Fibroblast response to various concentrations and presentation of mECMs was investigated by evaluating changes in viability, proliferation, cell phenotype, and cytokine secretion. Results: mECMs had reduced intensity in collagen I associated bands, indicating successful fragmentation to lower molecular weights. Soluble (mobile) mECMs induced changes in fibroblast phenotype as indicated by a decrease in proliferation, a decrease in nuclei area, and an increase in the percentage of elongated cells. In addition, mobile mECMs contributed to significant increases in cytokine secretion compared to insoluble (bound) mECMs. Across all experiments, bound mECMs exhibited effects on fibroblasts compared to the collagen control. Conclusion: Fibroblasts in vitro recognize mECMs, with significant differences observed based on the presentation of these proteins. These data indicate that cryptic regions that are recognized by fibroblasts may be exposed in the mobile version of the mECMs, which lead to a myofibroblast-like phenotype in fibroblasts. This work highlights the potential of DAMPs to serve as immunomodulatory therapeutics for tissue regeneration. 

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